Title: Efficacy of Allosteric SHP2 Inhibitor in RAS Mutant-Driven Myeloid Neoplasms Project Summary/Abstract Myeloid neoplasms are a group of stem cell-derived hematologic malignancies characterized by abnormal production of myeloid lineage cells. Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are aggressive myeloproliferative neoplasms (MPN) that have poor clinical outcome. Current chemotherapies are not adequate to treat CMML and JMML. Somatic mutations in RAS are found in ~40% of CMML and ~30% of JMML cases. Direct inhibition of oncogenic RAS has not been successful. Therefore, targeting of RAS regulator or effector could be a useful strategy in treating MPN driven by RAS mutants. Aberrant activation of the MEK/ERK pathway is commonly observed in RAS mutant expressing cells. Although MEK inhibitor treatment can reduce cell proliferation, it only partially improves MPN phenotype in KRAS mutant mice. Furthermore, MEK inhibitor treatment failed to reduce the RAS mutant hematopoietic progenitors in the bone marrow, and T-lineage acute lymphoblastic leukemia (T-ALL) emerged in some mice despite ongoing treatment. So, there is a need to identify new therapeutic target(s) and develop novel targeted therapies for oncogenic RAS-driven MPN (CMML and JMML). SHP2 regulates the RAS/RAF/MEK/ERK pathway. Genetic deletion or pharmacologic inhibition of SHP2 abrogates the activation of the RAS/RAF/MEK/ERK pathway. So, we hypothesize that inhibition of SHP2 might be useful in treating RAS mutant-driven MPN (CMML and JMML). To test our hypothesis, we propose two specific aims. Specific Aim 1 will determine the efficacy of allosteric SHP2 inhibitor SHP099 against RAS mutant hematopoietic cells/progenitors and KRasG12D knockin mouse model of MPN. Specific Aim 2 will determine the mechanism of inhibition of RAS mutant-driven MPN by SHP099 treatment. Our proposed studies will determine if targeting of SHP2 is effective against oncogenic RAS-driven MPN. Moreover, results from these studies will lay the groundwork for clinical trials of allosteric SHP2 inhibitor for treatment of CMML and JMML.